biostudies-literatureNewman JHNCI NIH HHSNIH HHS3672-3685https://www.ebi.ac.uk/biostudies/studies/S-EPMC10905627biostudies-literatureUnknown37(27)BMP receptor inhibitors induce death of cancer cells through the downregulation of antiapoptotic proteins XIAP, pTAK1, and Id1-Id3. However, the current most potent BMP receptor inhibitor, DMH2, does not downregulate BMP signaling in vivo because of metabolic instability and poor pharmacokinetics. Here we identified the site of metabolic instability of DMH2 and designed a novel BMP receptor inhibitor, JL5. We show that JL5 has a greater volume of distribution and suppresses the expression of Id1 and pTak1 in tumor xenografts. Moreover, we demonstrate JL5-induced tumor cell death and tumor regression in xenograft mouse models without immune cells and humanized with adoptively transferred human immune cells. In humanized mice, JL5 additionally induces the infiltration of immune cells within OncogeneNovel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer.PMC10905627R50 CA275877P30CA72720P30 CA072720Jhawar SRKerrigan JEMalhotra JLangenfeld EAugeri DJLangenfeld JTarabichi SDobias NSSadimin ETNeMoyer RJabbour SKGoedken MBommareddy PKLi SZloza AChesson CBMinerowicz CMarshall SCarayannopolous MONewman JHLee MJfalseNovel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer.BMP receptor inhibitors induce death of cancer cells through the downregulation of antiapoptotic proteins XIAP, pTAK1, and Id1-Id3. However, the current most potent BMP receptor inhibitor, DMH2, does not downregulate BMP signaling in vivo because of metabolic instability and poor pharmacokinetics. Here we identified the site of metabolic instability of DMH2 and designed a novel BMP receptor inhibitor, JL5. We show that JL5 has a greater volume of distribution and suppresses the expression of Id1 and pTak1 in tumor xenografts. Moreover, we demonstrate JL5-induced tumor cell death and tumor regression in xenograft mouse models without immune cells and humanized with adoptively transferred human immune cells. In humanized mice, JL5 additionally induces the infiltration of immune cells within 2018-01-01T00:00:00Z2018 Jul2025-04-05T11:38:27.223Z2025-04-05T11:38:27.223ZS-EPMC109056272962279710.1038/s41388-018-0156-9